Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia

• Published in: Journal of lipid research 2009-07, Vol.50 (7), p.1463-1471
• Main Authors: Tremblay, André J, Lamarche, Benoît, Hogue, Jean-Charles, Couture, Patrick
• Format: Article
• Language: English
• Subjects: Adult; Animals; Anticholesteremic Agents - therapeutic use; apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B - metabolism; Azetidines - therapeutic use; cholesterol absorption and synthesis; Cholesterol, LDL - blood; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; gas chromatography/mass spectrometry; Humans; Hyperlipidemias - drug therapy; Hyperlipidemias - metabolism; Hyperlipidemias - physiopathology; intestine; kinetic; Lipoproteins - blood; liver; Male; Patient-Oriented and Epidemiological Research; Placebos - therapeutic use; Simvastatin - therapeutic use; Treatment Outcome; Triglycerides - blood
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P800061-JLR200

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (−43.0%), LDL-C (−53.6%), and triglycerides (−44.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (−48.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (−38.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r = 0.85; P < 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.